Research in this program is focused on the basic mechanisms by which the host mobilizes and modulates cellular inflammatory reactions in defense against foreign antigens and infectious agents. In a multi-disciplinary, yet integrative approach, mechanisms of integrin adhesion, chemotaxis, signaling, mediator synthesis and apoptosis are explored in vitro and extended into experimental animal models (bacterial induced rodent arthritis; knockout and transgenic mice) for in vivo analysis. In addition, human conditions of chronic inflammatory disease in response to foreign implants, infectious pathogens, or of unknown etiology are explored at the cellular, molecular and biochemical levels. The pathogenesis of such chronic destructive lesions is profoundly complex and is also related to hormones, gender, immunogenetics, dysregulated immunity, demographics and age. Understanding the mechanisms which control normal immune cell recruitment, activation and/or deletion and the switch to pathogenesis underlies the development of strategies for modulating chronic pathogenic inflammatory diseases. In an experimental model of arthritis, we have successfully characterized the immunopathology and documented therapeutic intervention at several levels, including 1) inhibition of integrin-dependent adhesion and signal transduction by synthetic fibronectin peptides; 2) suppression of autotoxic NO by NMMA and hemoglobin; 3) inhibition of recruitment and inflammatory mediators by TGF-beta through systemic delivery, gene therapy, hCG or oral tolerance; 4) sequestration of TNF alpha by gene transfer of soluble TNF receptors; and 5) blockade of serine proteases by secretory leukocyte protease inhibitor (SLPI). As therapeutic immunomodulators, TGF-beta and SLPI appear particularly promising due to their spectrum of anti-inflammatory targets, and these are being further characterized in TGF-beta and SLPI null and transgenic mouse models.